Nuclear localization of human SOD1 and mutant SOD1-specific disruption of survival motor neuron protein complex in transgenic amyotrophic lateral sclerosis mice.
Nuclear localization of human SOD1 and mutant SOD1-specific disruption of survival motor neuron protein complex in transgenic amyotrophic lateral sclerosis mice.
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DOI：
10.1097/nen.0b013e318244b635
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发表时间：
2012-02
影响因子：
3.2
通讯作者：
Martin LJ
中科院分区：
文献类型：
--
作者：
Gertz B;Wong M;Martin LJ
肌萎缩侧索硬化症(ALS)是一种成人起病的致命性神经退行性疾病，可导致运动神经元变性和瘫痪。大约20%的家族性ALS病例与铜/锌超氧化物歧化酶(SOD1)基因突变有关，但尚不清楚该蛋白突变是如何导致运动神经元退化的。表达突变形式的人SOD1(HSOD1)的转基因(TG)小鼠表现出与ALS相似的临床和病理特征。我们使用表达hSOD1-G93A、hSOD1-G37R和hSOD1-野生型的TG小鼠来研究一种新的亚细胞病理，涉及突变型hSOD1蛋白显著定位于核室和破坏核宝石的构筑。我们建立了从小鼠中枢神经系统组织中提取相对纯的细胞核部分的方法，发现内源性SOD1在小鼠脑和脊髓中核存在低水平，而在TG小鼠中hSOD1-G93A、-G37R和-野生型存在显著的核聚集。HSOD1在很小的时候就集中在脊髓细胞的细胞核，特别是运动神经元。在hSOD1-G93A和-G37R小鼠中，存活运动神经元蛋白(SMN)复合体在疾病发病前在运动神经元核中被破坏；年龄匹配的hSOD1-野生型小鼠尽管有核存在，但没有表现出SMN破坏。我们的数据表明，在ALS模型小鼠中，新的机制涉及hSOD1在细胞核中的积累和突变型hSOD1特异性的SMN定位干扰以及核SMN复合体的破坏，并表明致病机制与脊髓性肌萎缩重叠。
Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease that causes degeneration of motor neurons and paralysis. Approximately 20% of familial ALS cases have been linked to mutations in the copper/zinc superoxide dismutase (SOD1) gene but it is unclear how mutations in the protein result in motor neuron degeneration. Transgenic (tg) mice expressing mutated forms of human SOD1 (hSOD1) develop clinical and pathological features similar to those of ALS. We used tg mice expressing hSOD1-G93A, hSOD1-G37R, and hSOD1-wild type to investigate a new subcellular pathology involving mutant hSOD1 protein prominently localizing to the nuclear compartment and disruption of the architecture of nuclear gems. We developed methods for extracting relatively pure cell nucleus fractions from mouse CNS tissues and demonstrate low nuclear presence of endogenous SOD1 in mouse brain and spinal cord, but prominent nuclear accumulation of hSOD1-G93A, -G37R and -wild type in tg mice. hSOD1 concentrated in nuclei of spinal cord cells, particularly motor neurons, at a young age. The survival motor neuron protein (SMN) complex is disrupted in motor neuron nuclei prior to disease onset in hSOD1-G93A and -G37R mice; age-matched hSOD1-wild type mice did not show SMN disruption despite a nuclear presence. Our data suggest new mechanisms involving hSOD1 accumulation in the cell nucleus and mutant hSOD1-specific perturbations in SMN localization with disruption of the nuclear SMN complex in the ALS model mice and suggest overlap of pathogenic mechanisms with spinal muscular atrophy.